Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers

Sci Rep. 2020 Jan 20;10(1):701. doi: 10.1038/s41598-020-57534-5.

Abstract

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Carcinoma, Renal Cell / genetics*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Hippo Signaling Pathway
  • Humans
  • Kidney Neoplasms / genetics*
  • Laser Capture Microdissection
  • Male
  • Mice
  • Mutation*
  • Neoplasm Transplantation
  • Neurofibromin 2 / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Sequence Analysis, DNA / methods
  • Signal Transduction
  • Trans-Activators / genetics
  • Transcription Factors / genetics
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Up-Regulation
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • NF2 protein, human
  • Neurofibromin 2
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Protein Serine-Threonine Kinases